Baicalin Induces Ferroptosis in Breast Cancer Through a Novel STAT3/HO-1/GPX4 Regulatory Axis.

Abstract

Breast cancer (BC) is a leading cause of cancer-related mortality worldwide. Ferroptosis is a non-apoptotic regulated cell death that has been linked to the progression of BC and represents a promising therapeutic target for this malignancy. Baicalin (BA) is recognized for its antioxidant, anticancer, and anti-inflammatory effect. Although the ferroptosis-mediated antitumor activity of BA has been widely demonstrated in various cancers, its potential to induce ferroptosis in BC remains unclear. To explore its regulation of ferroptosis in BC and identify the underlying mechanisms, we performed multi-dimensional experiments to investigate the mechanisms of BA-induced ferroptosis. Proliferatively, CCK-8 and colony formation assays were employed to measure the viability and reproductive capacity of cells, complemented by a nude mouse xenograft model for in vivo validation. Subsequently, we demonstrated BA-induced cell death via ferroptosis in vitro and in vivo in BC, accompanied by ROS and lipid peroxidation accumulation, GSH depletion, intracellular liable Fe2+ enrichment and mitochondrial damage. Notably, these effects were reversed by ferrostatin-1. The pan-caspase inhibitor Z-VAD-FMK and Fer-1 rescued BA-induced cell death, whereas necroptosis inhibitors necrosulfonamide and necroptosis inhibitor necrostatin-1 as well as autophagy inhibitor chloroquine did not exert such effects. Significantly, ferroptosis serves as the predominant cell death mechanism. Mechanistically, we performed network pharmacology analysis and molecular docking to explore the interaction between BA and STAT3/HO-1/GPX4. Functionally, BA effectively disrupted GPX4-dependent ferroptosis defense and induced BC cell death. As a natural compound modulating this ferroptosis-related axis, BA is a promising therapeutic alternative to conventional chemotherapy, which is limited by severe systemic toxicity. Collectively, this work reveals BA may regulate ferroptosis via the potential STAT3/HO-1/GPX4 signaling axis.